The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain cyclobutane analogs of D, E, and F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers, have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G.sub.2, which is subsequently converted to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). A number of the naturally occurring prostaglandins, including prostaglandins of the F series (such as PGF.sub.2.alpha.), the E series (such as PGE.sub.2) and the D series (such as PGD.sub.2) are known to lower IOP after topical ocular instillation, but can cause marked inflammation as evidenced by conjunctival edema or other untoward effects such as conjunctival hyperemia.
All of the natural prostaglandins known to reduce intraocular pressure, including prostaglandins of the F series (such as PGF.sub.2.alpha.), the E series (such as PGE.sub.2) and the D series (such as PGD.sub.2), have a core cyclopentane ring with alpha and omega chains attached at C-8 and C-12 respectively, as indicated in the following structures: ##STR1##
Currently, the relationship between prostaglandin receptor activation and IOP lowering effects is not well understood. Various publications have reported that PGD.sub.2 receptor activation leads to second messenger activation and in particular, to the stimulation of adenylate cyclase and resultant increases in cAMP levels (Thierauch, Prostaglandins and their Receptors: II. Receptor Structure and Signal Transduction, Journal of Hypertension, 12:1-5 (1994). Some believe that PGF.sub.2.alpha. receptor activation, on the other hand, leads to increased outflow of aqueous humor. Regardless of the mechanism, both PGD.sub.2 and PGF.sub.2.alpha. (and certain of its analogs) have been shown to lower IOP. See (for PGD.sub.2) Nakajima, Effects of Prostaglandin D.sub.2 and its analogue, BW245C, on Intraocular Pressure in Humans, Graefe's Archive Clinical Experimental Ophthalmology, 229:411-413 (1991); and (for PGF.sub.2.alpha.), Giuffre, The Effects of Prostaglandin F.sub.2.alpha. on the Human Eye, Graefe's Archive Ophthalmology, 222:139-141 (1985); and Kerstetter et al., Prostaglandin F.sub.2.alpha. -1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, 105:30-34 (1988).
Synthetic analogs of both the PGD.sub.2 and PGF.sub.2.alpha. types have been pursued in the art Nakajima, Effects of Prostaglandin D.sub.2 and its analogue, BW245C, on Intraocular Pressure in Humans, (Graefe's Archive Ophthalmology, 229:411-413 (1991)). Although both types of molecules lower IOP, they have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects have included, among others, an initial increase in IOP and conjunctival hyperemia, (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, 4(11):44-50 (1993)).
The relationship between EP receptor activation and IOP lowering effects is also the subject of some debate. There are currently four recognized subtypes of the EP receptor: EP.sub.1, EP.sub.2, EP.sub.3, and EP.sub.4 (Ichikawa, Sugimoto, Negishi, Molecular aspects of the structures and functions of the prostaglandin E receptors, J. Lipid Mediators Cell Signaling, 14:83-87 (1996)). It is known in the art that IOP may be lowered by ligands capable of EP.sub.2 receptor activation, such as PGE.sub.2 and certain of its synthetic analogs (Fallach, Eliason, Topical Prostaglandin E.sub.2 Effects on Normal Human Intraocular Pressure Journal of Ocular Pharmacology, 4(1):13-18 (1988)). Woodward, et al., Molecular Characterization and Ocular Hypotensive Properties of the Prostaglandin EP2 Receptor, Journal of Ocular Pharmacology and Therapeutics, 11(3):447-454 (1995)), or EP.sub.3 receptor activation (Woodward, et al., Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies, Journal of Lipid Mediators, 6:545-553 (1993)); Waterbury, et al., EP.sub.3 but not EP.sub.2 FP or TP Prostanoid-Receptor Stimulation May Reduce Intraocular Pressure, Investigative Ophthalmology and Visual Science, 31(12):2560-2567 (1990)). However, some of these molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing, including an initial increase in IOP, photophobia, and eye ache (see, for example, Flach, Eliason, Topical Prostaglandin E.sub.2 Effects on Normal Human Intraocular Pressure, Journal of Ocular Pharmacology, 4(1):13-18 (1988)).
A number of synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects in varying degrees which greatly limit their clinical utility. Based on the foregoing, a need exists for the development of molecules that may activate key prostaglandin receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
Attempts have been made by Stjernschantz et al. (U.S. Pat. No. 5,321,128), Woodward et al., (U.S. Pat. No. 5,093,329), Chan et al. (WO 92/08465) and Ueno et al. (EP 330 511 A.sub.2) to reduce selectively or to eliminate altogether the side effects while maintaining the IOP-lowering effect. The Stjernschantz et al. publication is of particular interest because it reports that certain prostaglandin analogs, which retain the alicyclic rings characteristic of natural prostaglandins but which possess modifications in the omega chain, still exhibit the intraocular pressure lowering activity of the natural prostaglandins and have fewer adverse effects. These synthetic prostaglandins, like their natural counterparts, all possess the core, five-membered ring. Six-membered ring (cyclohexane) analogs of D, E and F series prostaglandins for lowering IOP are disclosed in commonly owned U.S. application Ser. Nos. 60/049,913 and 60/049,912.
Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by natural D, E, and F series prostaglandins and their synthetic analogs while avoiding some or all of the undesirable side effects usually associated with the use of such compounds. An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other gents, is said to have an improved therapeutic profile. It is an object of this invention to provide a novel class of IOP lowering agents with an improved therapeutic profile over the natural prostaglandins and many of their synthetic analogs. A further object of this invention is to provide methods of using the novel compounds in the treatment of glaucoma and ocular hypertension. It has now unexpectedly been discovered that the presently claimed cyclobutane analogs of PGD, PGE, and PGF meet this objective. Certain cyclobutane analogs of prostaglandins have been reported in the literature (see, Guzman, et al., Synthesis of Cyclobutano Prostaglandins, Chemistry and Industry, 20:884-885 (1975); Greene et al., Total Synthesis of 11-Nor Prostaglandins, Tetrahedron Letters, 41:3755-3758 (1976); Reuschling et al., Synthese von Cyclobutanprostaglandinen, Tetrahedron Letters, 1:17-18 (1976); Depres et al., Synthesis of Ring Modified Prostaglandins, Tetrahedron, 37(3): 621-628 (1981); Reuschling et al. Prostaglandin analog cyclobutane derivative, (DE 2705675). The presently claimed compounds and methods, however, are neither disclosed nor suggested in the foregoing art.